Activation of melanocortin 1 receptor (MC1R) is known to exert broad anti-inflammatory and anti-fibrotic effects. The purpose of this study is to investigate the potential of dersimelagon, a novel oral MC1R agonist, as a therapeutic agent for systemic sclerosis (SSc). The effects of dersimelagon phosphoric acid (MT-7117) on skin fibrosis and lung inflammation were evaluated in bleomycin (BLM)-induced SSc murine models that were optimized for prophylactic and therapeutic evaluation. Microarray-based gene expression analysis and serum protein profiling were performed in the BLM-induced SSc models. The effect of MT-7117 on transforming growth factor-β (TGF-β)-induced activation of human dermal fibroblasts was evaluated in vitro. Immunohistochemical analyses of MC1R expression in the skin of SSc patients were performed. Prophylactic treatment with MT-7117 (≥ 0.3 mg/kg/day p.o.) significantly inhibited skin fibrosis and lung inflammation, and therapeutic treatment with MT-7117 (≥ 3 mg/kg/day p.o.) significantly suppressed the development of skin fibrosis in the BLM-induced SSc models. Gene array analysis demonstrated that MT-7117 exerts an anti-inflammatory effect via suppression of the activation of inflammatory cells and inflammation-related signals; additionally, vascular dysfunction was extracted as the pathology targeted by MT-7117. Serum protein profiling revealed that multiple SSc-related biomarkers including P-selectin, osteoprotegerin, cystatin C, growth and differentiation factor-15, and S100A9 were suppressed by MT-7117. MT-7117 inhibited the activation of human dermal fibroblasts by suppressing TGF-β-induced ACTA2 (encoding α-smooth muscle actin) mRNA elevation. MC1R was expressed by monocytes/macrophages, neutrophils, blood vessels (endothelial cells), fibroblasts, and epidermis (keratinocytes) in the skin of SSc patients, suggesting that these MC1R-positive cells could be targets for MT-7117. MT-7117 demonstrates disease-modifying effects in preclinical models of SSc. Investigations of its mechanism of action and target expression analyses indicate that MT-7117 exerts its positive effect by affecting inflammation, vascular dysfunction, and fibrosis, which are all key pathologies of SSc. The results of the present study suggest that MT-7117 is a potential therapeutic agent for SSc. A phase 2 clinical trial investigating the efficacy and tolerability of MT-7117 in patients with early, progressive diffuse cutaneous SSc is currently in progress.

中文翻译：

---

Dersimelagon 是一种新型口服黑皮质素 1 受体激动剂，在系统性硬化症的临床前模型中显示出疾病改善作用

已知黑皮质素 1 受体 (MC1R) 的激活可发挥广泛的抗炎和抗纤维化作用。本研究的目的是研究 dersimelagon（一种新型口服 MC1R 激动剂）作为系统性硬化症 (SSc) 治疗剂的潜力。在博莱霉素 (BLM) 诱导的 SSc 小鼠模型中评估了磷酸 dersmelagon (MT-7117) 对皮肤纤维化和肺部炎症的影响，该模型针对预防和治疗评估进行了优化。在 BLM 诱导的 SSc 模型中进行基于微阵列的基因表达分析和血清蛋白分析。在体外评估了 MT-7117 对转化生长因子-β (TGF-β) 诱导的人真皮成纤维细胞活化的影响。对 SSc 患者皮肤中的 MC1R 表达进行免疫组织化学分析。MT-7117 (≥ 0.3 mg/kg/day po) 预防性治疗显着抑制皮肤纤维化和肺部炎症，MT-7117 (≥ 3 mg/kg/day po) 治疗显着抑制皮肤纤维化的发展BLM 诱导的 SSc 模型。基因阵列分析表明，MT-7117 通过抑制炎症细胞的激活和炎症相关信号发挥抗炎作用；此外，血管功能障碍被提取为 MT-7117 靶向的病理。血清蛋白分析显示，MT-7117 抑制了多种 SSc 相关生物标志物，包括 P-选择素、骨保护素、胱抑素 C、生长和分化因子 15 和 S100A9。MT-7117 通过抑制 TGF-β 诱导的 ACTA2（编码 α-平滑肌肌动蛋白）mRNA 升高来抑制人真皮成纤维细胞的活化。SSc 患者皮肤中的单核细胞/巨噬细胞、中性粒细胞、血管（内皮细胞）、成纤维细胞和表皮（角质形成细胞）表达 MC1R，这表明这些 MC1R 阳性细胞可能是 MT-7117 的靶标。MT-7117 在 SSc 的临床前模型中表现出改善疾病的作用。对其作用机制和靶点表达分析的研究表明，MT-7117 通过影响炎症、血管功能障碍和纤维化发挥其积极作用，这些都是 SSc 的关键病理。本研究结果表明，MT-7117 是一种潜在的 SSc 治疗剂。